Early prediction of resistance to tyrosine kinase inhibitors by plasma monitoring of EGFR mutations in NSCLC: a new algorithm for patient selection and personalized treatment.

Fiamma Buttitta,Francesca Fabbri,Donatella Traisci,Luciana Irtelli,Francesco Malorgio,Alessia Di Lorito,Davide Brocco,Giovanni Cianci,Sonia Di Felice,Alessio Cortellini,Pietro Di Marino,Nicola D’Ostilio,Michele De Tursi,Antonio Marchetti,Alessandra Di Paolo,Pasquale Assalone,Lara Felicioni

doi:10.18632/oncotarget.27517

Abstract

In Non-Small-Cell Lung Cancer (NSCLC) patients treated with Tyrosine Kinase-Inhibitors (TKIs) therapy, the emergence of acquired resistance can be investigated by plasma monitoring of circulating tumor DNA (ctDNA). A series of 116 patients with EGFR-positive lung adenocarcinomas were treated with first/second generation EGFR TKIs. At clinical progression, 64 (55%) EGFR T790M plasma positive patients were subjected to second line-treatment with osimertinib and strictly monitored during the first month of therapy. Plasma analysis by the EGFR Cobas test showed in 57 (89%) cases a substantial decrease in the levels of the sensitizing EGFR mutant allele (sEGFRma), down to a not detectable value. These patients were defined as plasmatic good responders (PGR). In 7 (11%) patients, the sEGFRma did not drop to zero (plasmatic poor responders, PPR). In these latter cases, Massive Parallel Sequencing (MPS) analysis at the end of the first month and at clinical progression showed the presence of resistant-inducing mutations, including MET and HER2 gene amplification, KRAS and PIK3CA gene mutations. PPR showed disease progression in 5 (71%) cases, stable disease in 2 (29%) cases, and a shorter median Progression-free survival (PFS) (4.3 ± 1.1 months) than that observed in PGR (13.3 ± 1.2 months) (P < 0.0001). Our data indicate that plasma monitoring by a simple RT-PCR-based EGFR mutation test in the first month of treatment may be useful for a rapid identification of patients to be subjected to further characterization by MPS. A diagnostic algorithm for an early detection of resistance-inducing mutations and patient management is reported.

Highlights

EGFR mutations that confer sensitivity to tyrosine kinase inhibitors (TKI) in non-small cell lung carcinomas paved the way for a precision medicine approach in this neoplastic form
We have shown for the first time that Non-Small-Cell Lung Cancer (NSCLC) patients carrying EGFR mutations in tumor tissue and subjected to first-line treatment with EGFR TKIs, can be strictly monitored in the first days of treatment by repeated blood draws to quantify EGFR mutant alleles in plasma [5]
The 57 patients in which plasma was cleared of the sensitizing EGFR mutant allele (sEGFRma) within the first month of therapy were defined as plasmatic good responders

Summary

Introduction

EGFR mutations that confer sensitivity to tyrosine kinase inhibitors (TKI) in non-small cell lung carcinomas paved the way for a precision medicine approach in this neoplastic form. We have shown for the first time that NSCLC patients carrying EGFR mutations in tumor tissue and subjected to first-line treatment with EGFR TKIs, can be strictly monitored in the first days of treatment by repeated blood draws to quantify EGFR mutant alleles in plasma [5]. This accurate quantification of EGFR mutations has proven to be useful for early prediction of clinical response. These results strongly suggest that the amount of EGFR sensitizing mutations in plasma reflects the tumor burden and that the fluctuations in the levels of EGFR sensitizing mutations in plasma are closely related to tumor load variations [4,5,6,7,8]

Methods

Results

Conclusion